This Collaborative Merit Review Award for Research (I01) proposed in response to RFA BX-18-007 from the Veteran Health Administration is a joint effort by investigators from the JJ Peters VA Medical Center (Bronx, NY) Project 1, Arnold School of Public Health and Wm Jennings Bryan Dorn VA Medical Center (Columbia, SC) Project 2, Brain Science Center VA Medical Center (Minneapolis, MN) Project 3. We define a vision for an integrated and multidisciplinary program of preclinical research projects all linked by the ultimate goal to better characterize the mechanism of persistent and aberrant immunological activity in Gulf War Veteran Illnesses (GWVI) by developing experimental model systems, with the ultimate goal of developing novel therapeutic interventions. Gulf War Veterans? Illnesses is a multifaceted disorder characterized by a range of symptoms including cognitive impairment, fatigue, pain, mood disorders, among others. Recent evidence suggests that the onset and progression of these symptoms may be the result of disequilibrium in these subjects? immune systems. During deployment GWV were exposed to a unique variety of toxic agents that were specific to the Gulf War theatre, such as pyridostigmine bromine (PB), diisopropyl fluorophosphates (DFP), permethrin, and depleted uranium which current evidence indicates lowered thresholds to immunological responses and resulted in the persistent and heightened activity of certain arms of the immune system; a phenomenon best described as ?immunological priming?. In addition, they received more than 20 vaccines that could have overloaded the immune system. In support of these considerations, subjects with GWVI often have shown pathological signatures in common with autoimmune disorders and generalized inflammatory disorders, such as increased plasma concentrations of pro-inflammatory cytokines, unspecific tissue degeneration, and organ failure. Based on this concept, the three proposed collaborative research projects were designed to better understand how primed immune systems may contribute to GWVI- type phenotypes by exploring how multiple GWI conditions recapitulated in animal models may synergize and eventually provide new mechanistic evidence for translation studies. For example, Project 2 was designed to understand how GW toxin induced gut inflammasome activation causes gut dysbiosis and may lead to persistent or heightened immune-inflammatory responses and GWVI symptoms. As the goal of Project 3 is designed the hypothesis that lack of specific immunity leads to vaccine-induced inflammatory reaction in the brain, Project 2 will collaborate with project 3 to test the contribution of inflammasome priming and genetic diversity to gut dysbiosis and persistent immunological responses. Similarly, Project 1, which is designed to test how immunological priming may heighten inflammatory responses to psychological stressors, will collaborate with project 2 and project 3 by exploring how the NLRP3 inflammasome may contribute to heightened inflammation induced by gut dysbiosis or HLA polymorphisms, respectively. The outcome of these studies is of great interest not only because this will establish a novel link between inflammasome priming, genetic diversity and gut-dysbiosis toxemic response, but it will also provide insight to test novel therapeutic approaches that target the persistent activation of the immune system, either using immunotherapeutic approaches against vaccine toxins, probiotics to attenuate gut dysbiosis. Our proposed studies are innovative in terms of their scope, since it will fill the fundamental gaps needed for future translational studies. Most importantly our multiscale technological innovative approaches, which include knockout murine models of GWVI, including for the HLA and NLRP3 proteins, will enable our interdisciplinary research team with outstanding expertise in neuroscience, pharmacology, microbiology, chemistry to thoroughly investigate the molecular mechanisms underlying the etiology of GWVI.